Biologics in Refractory Vasculitis: A Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis

Phase 2TerminatedNCT05168475

Cambridge University Hospitals NHS Foundation Trust22 enrolled

Overview

Vasculitis occur when the body's immune system, rather than protecting the body, attacks blood vessels, causing injury to the vessel and the part of the body it supplies with blood. Vasculitis is rare, and there are a number of different types, which can affect both adults and children. We treat vasculitis with steroids and drugs aiming to damp down the activity of the immune system, but they often cause side effects. Some patients do not improve with this treatment, or cannot tolerate it and their vasculitis worsens; this is known as refractory vasculitis. Patients with refractory vasculitis are at high risk of health complications from the disease and its therapy and are in need of newer more effective treatments with fewer side effects. Biologics are drugs which are designed to precisely target parts of the immune system and may have fewer side effects. Biologics have been used for several years to treat vasculitis, particularly anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis or AAV. However, for many of the rarer types of vasculitis, and especially those vasculitis disease types that are not ANCA-associated, there is little information to support use of biologic therapies as effective treatments. The purpose of this trial is to find out whether biologics are effective and represent value for money for participants with refractory vasculitis. The trial will include patients with Non-ANCA-associated vasculitis (NAAV)

The trial is a multi-centre, randomised, double-blind, placebo-controlled, modified-crossover design which will investigate three biologics, Infliximab, Rituximab, Tocilizumab, and placebos to each, in the treatment of refractory non-ANCA-associated Vasculitis (NAAV) in adults and children. Eligible patients are randomised to a sequence of up to 4 interventions (comprising 3 biologics and 1 placebo to one of the three biologics being studied). Patients remain on first intervention in their randomised sequence for up to 2 years, or until they are deemed to fail treatment or experience a severe disease relapse, at which point they will be switched to the next intervention in their randomised sequence. When a patient switches to the next intervention in their randomised sequence, they will again remain on treatment either until the end of treatment period or until they fail treatment or experience a severe disease relapse. Patients remain on the treatment period for a maximum of 2 years, or until they have failed/experienced severe relapses on every treatment in their randomised sequence, whichever is sooner. Patients will be assessed for disease activity and relapse every 120 days up to D720.

Study Type

Eligibility

Sex: ALLMin age: 5 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Aged at least 5 years 2. Have given, or their parent/ legal guardian aged ≥ 16 years old has given, written informed consent 3. Diagnosis of NAAV (Appendix 4) 4. Refractory disease defined by: * Active disease, BVASv3-BIOVAS/ PVAS with ≥ 1 severe (new/worse) or ≥ 3 non-severe (new/worse) items despite 12 weeks of conventional therapy prior to screening visit OR * Inability to reduce prednisolone below 15mg/day or (0.2mg/kg/day in case of children) without relapse in the 12 weeks prior to screening visit Exclusion Criteria: 1. Previous treatment failure/contraindication to ≥ 2 active trial IMPs 2. Increase in the dose or frequency of background immunosuppressive (e.g. methotrexate) or anti-cytokine therapy within 30 days of screening visit 3. Use of intravenous immunoglobulins within 30 days, or cyclophosphamide or lymphocyte depleting biologic (e.g. rituximab) within 6 months of screening visit 4. Concomitant use of any biologic and/or anti-TNF agent other than the trial IMPs during the trial period 5. Have an active systemic bacterial, viral or fungal infection, or tuberculosis 6. Hepatitis B (HB) core antibody (Ab) or HB surface antigen positive or hepatitis C antibody positive or human immunodeficiency virus (HIV) antibody test positive 7. History of malignancy within five years prior to screening visit or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure 8. Pregnant or breastfeeding, or inability/unwillingness to use a highly effective method of contraceptive if a woman of childbearing potential (WOCBP;see section 11.9) 9. Severe disease, which in the opinion of the physician prevents randomisation to placebo 10. Recent or upcoming major surgery within 45 days of screening visit 11. Leukocyte count \< 3.5 x 109 cells/l, platelet count \< 100 x 109 cells/l, neutrophil count of \< 2 x 109 cells/l 12. ALT or ALP \> 3 times the upper limit of normal 13. Symptomatic congestive heart failure (NYHA class III/IV) requiring prescription medication within 90 days of screening visit 14. Demyelinating disorders 15. History or presence of any medical condition or disease which, in the opinion of the Investigator, may place the participant at unacceptable risk because of trial participation 16. Administration of live or live attenuated vaccines within 45 days of screening 17. Have received an investigational medicinal product (IMP) within 5 half-lives or 30 days prior to screening 18. Diagnosis of adenosine deaminase type 2 (DADA2) 19. Hypersensitivity to the active IMP substance or to any of the formulation excipients

Locations (5)

Cambridge University Hospitals NHS Foundation Trust

Cambridge, United Kingdom

Glasgow Royal Infirmary

Glasgow, United Kingdom

Great Ormond Street Hospital NHS Foundation Trust

London, United Kingdom

Guy's and St Thomas

London, United Kingdom

East Kent Hospitals

Margate, United Kingdom

Outcomes

Primary Outcomes

Treatment Failure

Primary treatment failure is progressive disease (defined by appearance of ≥1 new/worse severe or ≥3 new/worse non-severe items) on Birmingham vasculitis activity score (BVAS) v3 modified for BIOVAS trial (BVASv3-BIOVAS) or paediatric vasculitis activity score (PVAS) within 120 days from the time of IMP commencement; or failure to achieve clinical response (see definitions below) by 120 days from the time of IMP commencement. In such cases, TTF will be recorded as zero. We report this as number of events that occurred. As arms reached the number of events to define a median, we are reporting it as number of events.

Time frame: up to 720 days

Secondary Outcomes

Patients Achieving Response at the 120 Day Timepoint Following Commencement of IMP

Proportion of participants achieving response at the 120 day evaluation time point after the start of each IMP. The response status is defined by a BVAS v3-BIOVAS/ PVAS of ≤ one non-severe (no new/worse) item, prednisolone dose ≤ 50% of the dose at the start of the IMP treatment and ≤ 10mg/day (0.2 mg/kg/day for children, whichever is lower) and an ESR \< 30mm/hr or CRP \<10 mg/L

Time frame: 120 days

Patients Achieving Response at Any 120 Day Timepoint

Proportion of participants achieving response at every 120 day evaluation time point defined by a BVAS v3-BIOVAS/ PVAS of ≤ 1 non-severe (no new/worse) item, prednisolone dose ≤ 50% of the dose at the start of the IMP treatment and ≤ 10mg/day (0.2 mg/kg/day for children, whichever is lower) and an ESR \< 30mm/hr or CRP \<10 mg/L

Time frame: up to 720 days

Increase in Disease Related Damage Measured by Vasculitis Damage Index/Paediatric Vasculitis Damage Index (VDI/PVDI) From Start to End of an IMP Treatment

VDI/PVDI scores are collected from 11 different disease categories with each positive item scoring one mark. VDI/PVDI scores can either increase or stay the same at each measurement. All damage scores are carried forward to the next assessment. The minimum score is zero and the maximum score is 63. A low score indicates less damage and therefore a better outcome. A higher score indicates more damage and a worse outcome. Due to the study design, participants were kept on each intervention until treatment failure and then moved to the next in their allocated sequence. Secondary outcome data were collected from the start of the first treatment without restarting collection at each crossover. Therefore, results are presented by treatment sequence. The number of participants analysed includes all participants who received the given intervention at any time during the study.

Time frame: VDI/PVDI scores were collected every 120 days at each scheduled visit in the trial until the last assessment at day 720 at the end of trial. 120 days, 240 days, 360 days, 480 days, 600 days and 720 days

Physician's Global Assessment (PGA) (Likert Scale 0-10)

Physician's global assessment at every 120 day evaluation time point from the time of IMP commencement The Physician's global assessment (PGA) is a visual analogue scale from 0-10, where 0 is no disease activity (better outcome) and 10 is maximum disease activity (worse outcome). PGA scores are collected every 120 days at each scheduled visit for each participant (unless a visit is unscheduled which could occur at any time in between the time points). Due to the study design, participants were kept on each intervention until treatment failure and then moved to the next in their allocated sequence. Secondary outcome data were collected from the start of the first treatment without restarting collection at each crossover. Therefore, results are presented by treatment sequence. The number of participants analysed includes all participants who received the given intervention at any time during the study.

Time frame: 120 days, 240 days, 360 days, 480 days, 600 days, 720 days

Serious Adverse Events/Adverse Events of Special Interests (SAEs/AESIs)

Serious adverse events (SAEs) and adverse events of special interest (AESI) (where infection is considered an AESI)

Time frame: up to 720 days

Biologics in Refractory Vasculitis: A Trial of Biologic Therapy for Refractory Primary Non-ANCA Associated Vasculitis

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes